Enteroaggregative E. coli (EAEC) is a bacterium that can cause diarrhea. The purposes of this study are to: determine how much EAEC is needed to cause diarrhea in a healthy person, determine if a genetic factor is important in causing diarrhea, and to see how the body's defenses control EAEC. Participants include 25 healthy adults, ages 18-40. Volunteers will be assigned to 1 of 4 dose levels in groups of 5 volunteers each. One volunteer in each group will receive a sodium bicarbonate placebo solution. Volunteers will be admitted to the University Clinical Research Unit for up to 8 days. Volunteers will receive therapy with levofloxacin to treat the infection either once they develop diarrhea or at Day 5 if they remain asymptomatic. Study procedures will include saliva, blood, and fecal sample collection. An optional study procedure will include an intestinal biopsy. Participants will be involved in study related procedures for up to 223 days.

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Development of diarrhea defined as passage of one diarrheal stool containing at least 300 mL or 2 or more stools totaling 200 mL or greater passed during a 48-hour period within 96 hours after challenge. [ Time Frame: Assessed daily during the inpatient portion of the study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Increases in individual markers of inflammation: fecal leukocytes, lactoferrin and pro-inflammatory cytokines. [ Time Frame: At the conclusion of the challenge studies, once all specimens have been collected. ] [ Designated as safety issue: No ]

Proportion of subjects who receive rescue antibiotic therapy (defined as the initiation of antibiotic therapy when the primary outcome criteria listed above is met). [ Time Frame: Assessed daily during the inpatient portion of the study, Days 0-8 ] [ Designated as safety issue: No ]

Secretory IgA and humoral IgG response to homologous administered strain; expressed in titers. [ Time Frame: At the conclusion of the challenge studies, once all specimens have been collected. ] [ Designated as safety issue: No ]

Total volume of unformed stools passed during 5 days of study. [ Time Frame: Assessed daily during the inpatient portion of the study ] [ Designated as safety issue: Yes ]

Positive excretion of the administered test strain and number of days of excretion before antimicrobial is administered. [ Time Frame: Assessed daily during the inpatient portion of the study ] [ Designated as safety issue: No ]

Development of mild diarrhea defined as passage of any number of stools categorized as loose or watery but of less than 200 mL in addition to a complaint of one or more enteric symptoms. [ Time Frame: Assessed daily during the inpatient portion of the study ] [ Designated as safety issue: Yes ]

Dosages: 1X10^9, 5X10^9, 1X10^10, and 5X10^10 cfu; given in a sodium bicarbonate solution

Experimental: 2

Dosage 5X10^9 given orally in a sodium bicarbonate solution

Drug: Levofloxacin

Administered at a dose of 500 mg once a day for 3 days

Drug: Placebo

Sodium bicarbonate solution

Biological: Enteroaggregative E. coli (EAEC)

Dosages: 1X10^9, 5X10^9, 1X10^10, and 5X10^10 cfu; given in a sodium bicarbonate solution

Placebo Comparator: 5

Sodium bicarbonate placebo solution

Drug: Levofloxacin

Administered at a dose of 500 mg once a day for 3 days

Drug: Placebo

Sodium bicarbonate solution

Experimental: 4

Dosage 5X10^10 given orally in a sodium bicarbonate solution

Drug: Levofloxacin

Administered at a dose of 500 mg once a day for 3 days

Drug: Placebo

Sodium bicarbonate solution

Biological: Enteroaggregative E. coli (EAEC)

Dosages: 1X10^9, 5X10^9, 1X10^10, and 5X10^10 cfu; given in a sodium bicarbonate solution

Experimental: 3

Dosage 1X10^10 given orally in a sodium bicarbonate solution

Drug: Levofloxacin

Administered at a dose of 500 mg once a day for 3 days

Drug: Placebo

Sodium bicarbonate solution

Biological: Enteroaggregative E. coli (EAEC)

Dosages: 1X10^9, 5X10^9, 1X10^10, and 5X10^10 cfu; given in a sodium bicarbonate solution

Detailed Description:

Enteroaggregative Escherichia coli (EAEC) causes diarrhea in travelers from industrialized nations to developing countries, children of developing countries, and patients with HIV. Although infection responds to antibiotic therapy, increasing antibiotic resistance and the widespread nature of the infection limit the utility of antibiotics. The development of an EAEC-specific vaccine would be useful in the prevention of travel-associated EAEC diarrhea and in the decrease of EAEC-associated mortality in young children in the US and of developing countries. The first objective of the study is to perform a dose-escalation study of EAEC 042 infectivity in healthy adult volunteers who are high producers of IL-8 and seronegative to EAEC. The study will identify the dose of EAEC 042 needed for future studies on EAEC 042 such as phase I-II EAEC vaccine studies. The second objective of the study is to identify the humoral, secretory, and cellular immune response to EAEC 042 specific antigens that are associated with EAEC infection. Study participants will include 25 healthy volunteers, ages 18-40, from the greater Houston area. Study participants will be assigned to 1 of 4 possible dose levels in groups of 5 volunteers each. Each study group will consist of 4 volunteers receiving EAEC and 1 volunteer receiving a sodium bicarbonate placebo solution. Safety data and results will be reviewed by the safety monitoring committee before beginning the next highest dose group. If a dose results in at least 3 of the 4 infected volunteers of a given group, the next highest dose will not be administered. Instead, the concentration will be repeated for validation of the dose. Healthy volunteers will be screened as outpatients for the presence of the -251 AA SNP genotype in the IL-8 gene promoter. Once a volunteer has been screened and determined to be eligible to participate in the study, the volunteer will sign a consent form and be admitted at the University Clinical Research Unit. The volunteer will ingest a determined concentration of EAEC 042 or placebo and be observed for symptoms of infection. All volunteers will receive therapy with levofloxacin to eradicate the infection either once they develop diarrhea or at Day 5 if they remain asymptomatic. Volunteers will be discharged from the hospital on Day 7+/-1. Saliva, blood, and feces will be collected for secretory, humoral, and cellular immune responses to EAEC. An optional procedure will consist of obtaining jejunal and colonic biopsies prior to challenge (Day -13±2) and Days 4±1 and 24±3 post challenge. Volunteer participation in endoscopy studies will be optional and will not be a requirement for the rest of the study. The primary endpoints of the study include: diarrheal illness after exposure to EAEC, shedding of EAEC after exposure, and IgG and secretory IgA (slgA) seroconversion to EAEC dispersin. The secondary endpoints of the study include: increase in fecal markers of intestinal inflammation including cytokines and lactoferrin and description of the jejunal and colonic immune response to EAEC infection.

Must accomplish all laboratory and diagnostic examinations at 21± 7 days prior to admission or enrollment.

Be at least 18 years of age but not older than 40 years of age at the time of enrollment.

Be otherwise healthy with a stable address and telephone where the volunteer can be contacted.

Be able to read and write English.

Possess a social security number in order to receive compensation.

Female participants must have a negative serum pregnancy test at screening and a negative urine pregnancy test on the morning of the challenge and use effective birth control during the entire study period. Methods of effective birth control include: complete abstinence, the use of a licensed hormonal method, intrauterine device, barrier method plus spermicide, or having sexual relations exclusively with a vasectomized partner. Appropriate barrier methods include condoms, cervical sponge, and diaphragm. Females who are not of childbearing potential are defined as those who are physiologically incapable of becoming pregnant, including any female with tubal ligation or who is postmenopausal. For purposes of this study, postmenopausal status will be defined as absence of menses for at least 1 year.

Has used medications or drugs, including over-the-counter medications such as decongestants, antacids (calcium carbonate or aluminum-based antacids, H2 blockers), anti-diarrheal medications (such as bismuth subsalicylate or loperamide), antihistamines within 7 days of challenge.

Depression not controlled with current drug therapy or involving institutionalization

Schizophrenia or psychosis

Suicide attempt.

Has a history of or current alcohol or illicit drug abuse.

Is unable to remain as an inpatient in the University Clinical Research Unit for up to 8 days.

Has a known hypersensitivity to latex, heparin, opiates, antiemetics, benzodiazepines, lidocaine, magnesium citrate, or Fleet enema.

Has a known hypersensitivity to antibiotics that could be used to treat EAEC infection including fluoroquinolones, amoxicillin, cephalosporins or rifaximin.

Has serum antibodies to EAEC dispersin.

Recently traveled to a developing country (within 6 months).

Has household contacts who are less than 4 years of age or more than 80 years of age.

Has household contacts that are infirmed or immunocompromised due to any of the following reasons:

Corticosteroid therapy

HIV infection

Cancer chemotherapy

Other chronic debilitating diseases.

Works as health care personnel with direct patient care.

Works in a day care center for children or the elderly.

Is a food handler.

Has factors that, in the opinion of the investigator or research personnel, would interfere with the study objectives or increase the risk to the volunteer or his contacts.

Is currently participating in a clinical study or had receipt of an investigational drug in the past 30 days.

Is pregnant or has a risk of pregnancy or is lactating.

Has current excessive use of alcohol or drug dependence.

Has evidence of impaired immune function.

Has a new positive reaction to purified protein derivative (PPD) (volunteers who are known to be PPD positive that have a negative chest x-ray and have received isoniazid prophylaxis will be eligible).

Has a stool culture that demonstrates the presence of pathogenic ova, pathogenic parasites, or bacterial enteropathogens (EAEC, Salmonella, Shigella, and Campylobacter), or that is devoid of normal flora.

Has self-reported lactose or soy intolerance or allergy

Is a smoker and cannot stop smoking for the duration of the inpatient study.

Has abnormal lab results for screening beyond the normal range as defined below:

Urinalysis Urine color: Yellow Turbidity: Clear pH: 5.0-8.0 Protein: Negative Sp. Gravity: 1.003-1.030 Glucose: Negative WBC: 0-2 Cells per HPF RBC: 0 Cells per HPF Bacteria: Rare Ketones: Negative The urinalysis will initially be evaluated for the quality of collection. If urinalysis is found to be poorly collected and demonstrates the presence of squamous epithelial cells and bacteria, results will not be used and a repeat urinalysis will be requested. In the case of menstruating women, the urinalysis collection will be postponed temporarily. A urinalysis may also be repeated once if traces of bile, protein, trace ketones, or Hb are identified. In the case of a properly collected urinalysis, the presence of leukocyte esterase glucose, or nitrates will exclude the participation of the subject.

Develops a febrile illness during the period of time screening period and prior to challenge.

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00362869